Chagas disease is a vector-transmitted tropical disease caused by Trypanosoma cruzi. 
Historically, Chagas disease has been regarded as largely affecting people living in rural areas of Latin America, primarily rural areas of Central and South America. The symptoms of the disease are silent and can appear many years after infection.
Chagas disease is expanding beyond its endemic area as a result of migration from and to the endemic countries (Hotez, 2008; Schofield and Kabayo, 2008). In addition, the World Health Organization (WHO) reports that blood donations and poor safety in blood banks have led to infections with Chagas disease in countries outside Latin America as some people who may be unaware they carry the infection have donated their blood to the national blood supply. As a result, the disease has now appeared in several countries in Europe and various parts of the United States of America.
A hematophagous insect (such as a triatomine insect) takes a blood meal from a vertebrate host infected with Trypanosoma cruzi and becomes a vector for Chagas disease. The insect ingests trypomastigotes from an infected vertebrate host, which proliferate and transform into the epimastigote form and then transform into the metacyclic trypmastigote form. The feces from the vector contain metacyclic trypomastigotes that can contaminate a bite or wound and pass into a vertebrate host (a mammalian “reservoir,” which can be a human). The metacyclic trypomastigotes penetrate various cells at the bite or wound site and transform into amastigotes, which multiply by binary fission in cells of infected tissue. The intracellular amastigotes transform into trypomastigotes that then burst from the cells into the bloodstream. Clinical manifestations can result from the repetitive infective cycle in an infected vertebrate host.
Once an individual has contracted Chagas disease, the infection may remain relatively dormant, in some cases for decades. Many people who have the disease do not know they are infected. Chagas disease is a silent killer that causes the slow swelling of its victims' internal organs causing their eventual death. Most people later develop cardiac complications, resulting in disability and even death. Intestinal complications are also known to develop in patients resulting in an enlarged oesophagus or colon which make it difficult for the person to eat normally or pass stool.
There are currently two drugs used in the treatment of Chagas disease, benznidazole and nifurtimox. Where Chagas disease is endemic one of the two is used to treat disease victims. WHO has reported the two drugs (nifurtimox and benznidazole) are currently used to treat early stages of Chagas disease and that studies are being conducted for efficacy in treating later states of the disease. More recent literature reports the two drugs may be used to treat the acute phase of the infection where parasites (trypomastigotes) are detectable in the peripheral blood (Andrade et al., 2004; Schofield and Kabayo, 2008).
Nifurtimox is a 5-membered nitrofuran compound that is orally administered for 30 to 60 days. Benznidazole is an orally administered antiparasitic medication formerly marketed under the brand names Rochagan and Radanil. Benznidazole is reportedly effective in the acute or early chronic stage of infection with decreased effectiveness during late chronic phase. Recently, the emergence of Trypanosoma cruzi strains resistant to benznidazole have been reported. Both drugs have gastrointestinal and neurological side effects which may worsen as the patient ages. There are problems of non-compliance and there is no prescribed approved pediatric formulation.
Treatment is complicated due to high costs and side effects. Therapy mostly depends on the two known drugs developed decades ago that require long term administration, and are not available to all patients due to their high cost.
Consequently, there is a search for alternative drugs with efficacy against Trypanosoma cruzi and, in particular, drugs having a more selective mode of action. In the on-going search for alternatives, several classes of drug-like molecules have been considered. For instance, the naturally occurring lapachol (FIG. 1), and some of its derivatives reportedly show trypanocidal activity against T. cruzi (Salas et al., 2008). Use of naphthofuranquinones synthesized from 2-hydroxy-3-allyl-1,4-naphthoquinone against the epimastigote and trypomastigote forms of T. cruzi has been reported (Silva et al., 2006). A study involving 2,3-diphenyl-1,4-naphthoquinone against T. cruzi epimastigotes at a low micromolar concentration (LD50=2.5 μM) by inhibiting T. cruzi lipoamide dehydrogenase (TcLipDH) has been reported (Ramos et al., 2009). Still other efforts are focusing on other structurally diverse compounds, including other natural products (canthinones, catechin, hinokinin, as examples) and pyrimidine derivatives (fenarimol, as an example), and additional structurally diverse compounds. Other literature includes Menna-Barreto et al., 2009.
Despite a number of efforts, relating the structure and efficacy and selectivity of compounds for treating Chagas disease remains elusive and results can be unpredicatable.
In particular, there remains a need for appropriate chemotherapeutic treatment that can be used in Trypanosoma cruzi-infected patients, especially for slowing the progress of Chagas disease and for arresting development of severe forms of Chagas disease.
This situation establishes the unfulfilled need for new chemotherapeutic agents against Trypanosoma cruzi. 